REVI EW ARTI CLE

Nonsteroidal Anti-Inammatory Drugs,

Gastroprotection, and BenetRisk
Robert Andrew Moore, DSc*; Sheena Derry, MA*; Lee S. Simon, MD

;
Paul Emery, MD

*Pain Research and Nufeld Division of Anaesthetics, University of Oxford, Oxford, U.K.;

SDG LLC, Cambridge, Massachusetts U.S.A.;

Institute of Rheumatic and Musculoskeletal
Medicine, University of Leeds, NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds
Teaching Hospitals NHS Trust, Chapel Allerton Hospital, Leeds, U.K.
& Abstract
Background: Gastroprotective agents (GPA) substantially
reduce morbidity and mortality with long-term nonsteroidal
anti-inammatory drugs (NSAIDs) and aspirin.
Objective: To evaluate efcacy of NSAIDs, protection
against NSAID-induced gastrointestinal harm, and balance
of benet and risk.
Methods: Free text searches of PubMed (December 2012)
supplemented with related citation and cited by facili-
ties on PubMed and Google Scholar for patient requirements,
NSAID effectiveness, pain relief benets, gastroprotective
strategies, adherence to gastroprotection prescribing, and
serious harm with NSAIDs and GPA.
Results: Patients want 50% reduction in pain intensity and
improved fatigue, distress, and quality of life. Meta-analyses
of NSAID trials in musculoskeletal conditions had bimodal
responses with good pain relief or little. Number needed to
treat (NNTs) for good pain relief were 3 to 9. Proton pump
inhibitors (PPI) and high-dose histamine-2 receptor antago-
nists (H
2
RA) provided similar gastroprotection, with no
conclusive evidence of greater PPI efcacy compared with
high-dose H
2
RA. Prescriber adherence to guidance on use of
GPA with NSAIDS was 49% in studies published since 2005;
patient adherence was less than 100%. PPI use at higher
doses over longer periods is associated with increased risk of
serious adverse events, including fracture; no such evidence
was found for H
2
RA. Patients with chronic conditions are
more willing to accept risk of harm for successful treatment
than their physicians.
Conclusion: Guidance on NSAIDs use should ensure that
patients have a good level of pain relief and that gastropro-
tection is guaranteed for the NSAID delivering good pain
relief. Fixed-dose combinations of NSAID plus GPA offer one
solution. &
Key Words: pain, joint pain, nonsteroidal anti-inamma-
tory drugs, NSAID, gastroprotection, riskbenet analysis,
systematic review
Address correspondence and reprint requests to: Robert Andrew
Moore, DSc, Pain Research and Nufeld Division of Anaesthetics, Nufeld
Department of Clinical Neurology, University of Oxford, The Churchill,
Oxford OX3 7LE, U.K. E-mail: andrew.moore@ndcn.ox.ac.uk.
Disclosures: Horizon Pharma provided funding for this study but had
no inuence on its content; the company did have the right to see the
nished manuscript before publication, but not to enforce changes or
prevent publication. Andrew Moore, Lee Simon, and Paul Emery have had
specied relationships with Horizon and have received nancial reim-
bursement. Andrew Moore is an owner of Oxford Medical Knowledge,
who was paid for the work on this study. Lee Simon and Paul Emery were
paid consultants to Horizon Inc. RAM has provided expert advice for
Menarinin, Pzer, and MSD. PE has undertaken clinical trials and provided
expert advice for Pzer, MSD, Abbvie, UCB, BMS, Roche, Novartis. Sheena
Derry has no disclosures.
Submitted: April 30, 2013; Revision accepted: June 03, 2013
DOI. 10.1111/papr.12100
2013 The Authors
Pain Practice published by Wiley Periodicals, Inc. on behalf of World Institute of
Pain, 1530-7085/14/$15.00
This is an open access article under the terms of the Creative Commons
Attribution-NonCommercial License, which permits use, distribution and
reproduction in any medium, provided the original work is properly cited and
is not used for commercial purposes.
Pain Practice, Volume 14, Issue 4, 2014 378395
INTRODUCTION
Pain is one of the leading factors contributing to the
global burden of disease as measured by years lived with
disability.
1
Among the top 11 disorders contributing the
greatest burden include low back pain, neck pain, other
musculoskeletal disorders, migraine, and osteoarthritis.
These patients want very considerable reductions in
their pain,
2
and nonsteroidal anti-inammatory drugs
(NSAIDs) represent one major class of analgesic drugs
used in these conditions.
There is a well-understood spectrum of gastrointes-
tinal harm associated with use of NSAIDs, including
gastrointestinal symptoms, increased incidence of endo-
scopic ulcers, bleeding, and death.
3,4
A number of
different upper and lower gastrointestinal outcomes are
now recognized together as clinically signicant upper
and lower GI events (CSULGIEs); incidence rates can
vary between NSAIDs, and the background rate without
NSAID in clinical trials is about 0.3%.
5
A history of
prior gastrointestinal symptoms or bleeding, the pres-
ence of other risk factors like advancing age, higher
doses of NSAID, and probably duration of NSAID use
all increase the risk of upper gastrointestinal bleeding.
6
Individual NSAIDs come with different innate risks,
most likely related to the half-life of the drug. Table 1
used information from 2 systematic reviews with
different time periods
6,7
and some selected recent case
control studies that give results by individual drugs.
810
We have evidenced that the risk of upper gastrointestinal
(GI) bleeding events with ibuprofen at doses up to
2,400 mg is equivalent to that for diclofenac at doses up
to 100 mg daily. For naproxen doses up to 1,000 mg
and piroxicam at doses up to 20 mg daily, risks are
higher.
There is a signicant increased risk of GI bleeding
with use of NSAIDs, against a background that is not
insignicant (even within the context of randomized
trials, which frequently exclude patients at higher risk),
where the annual rate of complicated upper gastroin-
testinal events with NSAIDs can be around 1%.
11,12
There is an appreciable mortality.
3,13
Extensive use of gastroprotective agents (GPA) can
substantially reduce the morbidity and mortality asso-
ciated with long-term NSAID and aspirin use.
14
In the
U.K., the National Institute for Health and Care
Excellence (NICE) guidance on osteoarthritis suggests
coprescription with a proton pump inhibitor (PPI) in
every patient, irrespective of risk and whether the
patient is prescribed an NSAID or a coxib.
15
Other
guidance consistently advises the use of GPA with
NSAIDs when there is any gastrointestinal risk factor,
such as older age. Recent cohort studies in France and
Japan demonstrate very signicant population-based
reductions in upper gastrointestinal bleeding through
extensive and appropriate prescribing of PPI.
16,17
This article brings together evidence about a number
of different aspects of NSAIDs and protection against
gastrointestinal harm induced by NSAIDs, and exam-
ines the balance of benets and risks for their use. The
manuscript will be informed by evidence compiled from
systematic reviews and meta-analyses, paying particular
regard to contemporary standards of evidence.
The main areas of interest for the review include
evidence about the treatment outcome desired by
patients with chronic pain, results obtained with NSA-
Table 1. Meta-Analyses and Studies Indicating Increased Risk of Upper Gastrointestinal (GI) Bleeding
Study
(number of participants) Details
Relative Risk or Odds Ratio
Ibuprofen
2,400 mg
Diclofenac
100 mg
Naproxen
1,000 mg
Piroxicam
20 mg Current NSAID use
Hernandez-Diaz and
Rodrguez
6
( 80,000)
Overview of epidemiology
studies in 1990s
2.1 (1.6 to 2.7) 3.1 (2.0 to 4.7) 3.5 (2.8 to 4.3) 5.6 (4.7 to 6.7) 4.2 (3.9 to 4.6)
Lewis et al., 2004
(N = 8,349)
8
Individual patient meta-analysis of
3 retrospective casecontrol
studies
1.8 (0.8 to 3.7) 3.2 (1.9 to 5.8) 5.4 (2.9 to 9.9) 12 (6.5 to 22) 5.6 (4.6 to 7.0)
Lanas et al.
9
(N = 8,309)
Casecontrol study of national
health system in Spain
4.1 (3.1 to 5.3) 3.1 (2.3 to 4.2) 7.3 (4.7 to 11) 13 (7.8 to 20) 7.3 (4.0 to 13)
Garcia-Rodriguez and
Barreales Tolosa
10
(N = 11,561)
Casecontrol study using U.K.
database
2.0 (1.4 to 2.9) 3.7 (3.0 to 4.3) 8.1 (4.7 to 12) Not given 2.6 (1.9 to 3.6)
Masso Gonzalez
et al., 2010
7
( 40,000)
Systematic review of
epidemiological studies
2000 to 2008
2.7 (2.4 to 3.0) 4.0 (3.5 to 4.4) 5.2 (4.3 to 6.2) 9.3 (7.5 to 11) 4.6 (4.3 to 4.9)
NSAID, nonsteroidal anti-inammatory drugs.
NSAID, GPA, and BenetRisk 379
IDs based on these expected outcomes, collateral ben-
ets obtained, efcacy of PPI and histamine-2 receptor
antagonist (H
2
RA) gastroprotection, how well doctors
and patients adhere to gastroprotection guidelines and
therapy, other risks or rare but serious harm with
NSAIDs and GPAs, and patient attitudes toward risk
and benet in chronic conditions.
METHODS
We used several methodological techniques to maximize
the relevance of the review. These involved systematic
searching in a number of different areas, including using
data from existing reviews of randomized double-blind
trials for evidence of NSAID and gastroprotection
efcacy, and broad acceptance of other study designs
where appropriate. We followed PRISMA (Preferred
Reporting Items for Systematic Reviews and Meta-
analysis) statement guidelines where this guidance
applied
18
and high standards for evidence for NSAID
efcacy.
19,20
Literature Search
Searching for relevant studies was conducted with
several different themes, namely for patient-level
requirements for outcomes in chronic pain, individual
patient data analysis of NSAID effectiveness in chronic
pain conditions, benets of pain relief, gastroprotective
strategies used with NSAIDs, doctor and patient adher-
ence to gastroprotection prescribing and use, and for
rare, but serious adverse events associated with NSAIDs
and GPA. These searches comprised different free text
searches of PubMed (to December 2012), with follow-
up on any potentially useful publication using the
related citation and cited by facilities on PubMed.
For those articles deemed useful, we also checked on
citations of that publication using Google Scholar. In
addition to electronic searches, retrieved articles were
read for any other sources of data, as were general
reviewarticles and book chapters. Observational studies
can be poorly elicited by electronic searching,
21,22
and
our experience
22,23
is that this strategy captures a very
high proportion of high quality, large studies.
Study Selection
Publication in 1995 or later was required to accurately
reect evidence relevant to pain management in 2013.
Where possible, extant systematic reviews and
meta-analyses were sought, updated with any more
recent information where available. Any study architec-
ture was permitted, as appropriate for the subject. For
example, when examining the effect of pain treatment
on quality of life, the only architectures deemed appro-
priate were individual patient analysis of randomized
trials or large comprehensive cohort studies with clear
denition of inclusion criteria. For effect of NSAIDs or
GPA, only data from randomized trials were deemed
appropriate.
A single reviewer (RAM) was responsible for initial
study selection and for data extraction, but other
authors checked decisions over inclusion and accuracy
of data extraction.
Quality Assessment
The assessment of quality in observational studies is not
straightforward, and no ideal universal quality scoring
system exists.
24
We used study size in judging results
because small size is associated with a large potential for
random chance effects, whatever the study architec-
ture.
24
We chose to concentrate on those aspects most
likely to provide unbiased studies.
For comparative trials, we used only randomized,
double-blind trials and had a description of withdrawals
and dropouts, scoring at least 3/5 on the Oxford Quality
Scale.
25
Data Analysis and Presentation
For NSAID effectiveness, we used responders dened as
patients demonstrating a 50% reduction in pain inten-
sity, as this has become a validated outcome important
to patients.
19
However, no worse than mild pain may
be a better outcome. In this denition, withdrawal from
treatment for any reason is regarded as nonresponse and
equivalent to baseline observation carried forward
(BOCF), as imputation with the baseline level of pain
intensity would exclude achievement of any of these
levels of response. Responders were considered true
responders if they experienced benet and continued
taking the drug. Imputation using last observation
carried forward (LOCF), which the last nonmissing
observation is carried forward from the time of with-
drawal to the end of the trial, was not used because it has
shown to introduce signicant bias in some circum-
stances.
20
Analysis of the effects of PPI and H
2
RA in reducing
NSAID-induced endoscopic ulcers used endoscopic
380 MOORE ET AL.
outcomes ideally measured at 12 weeks or later to
capture appropriate benecial effects of long-term
therapy; studies or data before 6 weeks of NSAID and
GPA treatment were not included. Any dose of any PPI
was allowed, as long as it was equivalent to at least
20 mg omeprazole daily. For H
2
RAs, only high doses
were allowed in the analysis, equivalent to 80 mg of
famotidine or 600 mg ranitidine daily.
When pooling data, clinical homogeneity was exam-
ined graphically.
26
Relative benet (or risk) and number
needed to treat to prevent one endoscopic ulcer (NNTp)
were calculated with 95% condence intervals. Relative
benet or risk was calculated using a xed effects
model,
27
with no statistically signicant difference
between treatments assumed when the 95% condence
intervals included unity. We added 0.5 to treatment and
comparator arms of trials in which at least one arm had
no events. Number needed to treat (or harm) was
calculated by the method of Cook and Sackett,
28
using
the pooled number of observations only when there was
a statistically signicant difference of relative benet or
risk (where the condence interval did not include 1).
Signicance of differences between NNTs was calcu-
lated using the statistical z-test.
29
RESULTS
Patient Desired Outcomes in Chronic Pain
A systematic review of studies on patient expectations
indicates that large reductions in pain intensity, or being
in a low pain state (no worse than mild pain), are
consistently regarded as what chronic pain patients
desire from treatment.
30
The ideal of being good
rather than just better has been suggested previously
in rheumatology.
31
Long-term reduction in pain inten-
sity by 50% or more, together with concomitant
reduction in fatigue, distress, and the loss of quality of
life that accompanies chronic pain, is what patients
want from treatment.
3235
Patients agree that a clinically important difference
in pain outcomes would be at least a 33% level
suggested in breakthrough pain,
36
or more than 40/
100 mm (4/10 cm) reduction in pain, dened as much
better in musculoskeletal pain.
37
In bromyalgia, pain
severity reductions of about 40% were regarded as
clinically important.
38
For painful diabetic neuropathy
and bromyalgia, patients describing themselves as
much or very much better typically had pain intensity
reductions of 40% or more.
39
These are far greater than
the minimally important difference of a 6% reduction in
pain, suggested by patients with rheumatoid arthritis.
40
The patient acceptable symptom state (PASS) is
dened as the value beyond where patients consider
themselves well. For osteoarthritis, the junction between
satisfactory and unsatisfactory was about 32/100 mm
(3.2/10 cm).
41
Similar results were obtained with
numerical rating and function scales.
42
In chronic pain, we dene response as having both a
large reduction in pain intensity of at least 50% (some-
times at least 30%) from baseline and either freedom
from adverse events orat worstadverse events that
are tolerable, allowing the patient to continue with
therapy.
19,20
The Initiative on Methods, Measurement,
and Pain Assessment in Clinical Trials (IMMPACT)
group has dened 30% and 50% decrease in pain
intensity, respectively, as moderately important and
substantial improvements,
43
although more complex
responder denitions have also been sought.
44
When asked to rate how they imagine chronic pain
might affect quality of life, members of the public
without pain indicated that they considered pain scores
greater or equal to 4 or 5 of 10 would have increasingly
large detrimental effects.
45
The consistent message from the literature is that a
large reduction in pain intensity is an important and
desired outcome for patients.
Responder Analyses with NSAIDs
Several meta-analyses of individual patient data from
several randomized trials have provided information on
responder analyses with NSAIDs and cyclooxygenase-2
specic inhibitors (coxibs) in chronic pain conditions of
osteoarthritis of the knee, hip,
46
hand,
47
chronic low
back pain,
48
ankylosing spondylitis,
49
or antiepileptics
in bromyalgia.
50
These responder analyses provide 2
important insights:
1. Some people in trials get very large pain intensity
benets while others do not. Typically, there is no
Gaussian frequency distribution of benet. Fig-
ure 1 shows bimodal distributions of response in
postoperative pain,
51
osteoarthritis,
46
chronic
low back pain,
48
and ankylosing spondylitis.
49
This bimodal distribution is found in almost all
acute and chronic pain conditions.
2. As a consequence of the bimodal distribution,
only a few patients achieve a high level of
response with any particular therapy. The drugs-
specic (active minus placebo) proportion of
NSAID, GPA, and BenetRisk 381
patients achieving at least 50% pain intensity
reduction with NSAIDs varies from about 30% in
ankylosing spondylitis, 20%in osteoarthritis with
NSAIDs, to 10% in chronic low back pain and
bromyalgia.
50
Table 2 shows that because most treatment-specic
responses are low, numbers needed to treat (NNTs) for
effective treatment of chronic pain conditions with
NSAIDs are in the range of about 3 to 9. Few are better;
the exception may be NSAIDs in ankylosing spondylitis
where the NNT is about 3 for at least 50%pain intensity
reduction.
49
There is a consistent bimodal pattern of response with
NSAIDs in chronic musculoskeletal conditions. Some
patients have very good pain relief with NSAIDs. The
pattern that some patients respond to drug therapy, while
others donot, is broadlyrecognizedinpainandelsewhere.
52
Pain Relief and Other Benets
Information was obtained from a comprehensive review
of a series of linked systematic reviews examining
chronic pain prevalence, impact, cost, and the benets
of successful treatment.
53
Information examining the
benecial effects of successful treatment derived from13
studies with 7,586 patients with conditions including
migraine, bromyalgia, neuropathic pain, osteoarthritis,
rheumatoid arthritis, chronic low back pain, and anky-
losing spondylitis. There was a consistent link between
good pain relief and some aspect of well-being, includ-
ing activities of daily living or enjoyment of life,
<15%
15-29%
30-49%
50%
0 10 20 30 40 50 60 70
Percent with outcome
Etoricoxib 120 mg Placebo
<15%
15-29%
30-49%
50%
0 10 20 30 40 50 60 70
Percent with outcome
Naproxen 1000 mg Placebo
<15%
15-29%
30-49%
50%
0 10 20 30 40 50 60 70
Percent with outcome
Etoricoxib 60 mg Placebo
Postoperative pain Osteoarthritis pain
Chronic low back pain Ankylosing spondylitis
<15%
15-29%
30-49%
50%
0 10 20 30 40 50 60 70
Percent with outcome
Naproxen 1000 mg Placebo
Figure 1. Bimodal distribution of pain intensity reduction (Y-axis) of patients in acute postoperative pain, or chronic musculoskeletal
pain, with nonsteroidal anti-inammatory drug or coxib.
382 MOORE ET AL.
improved mood, sleep, functioning, quality of life,
work, and less fatigue. All of the studies reported some
link between pain relief and aspects of improved
functioning or quality of life.
The magnitude of the improvements reported is not
trivial and is perhaps best explained using the quality-
adjusted life year (QALY), which has a scale from 1
(perfect health for 1 year) to 0 (death). Health status
increases over 1 year were 0.22 with successful tumor
necrosis factor (TNF) inhibitor in rheumatoid arthri-
tis,
54
0.35 for 50% pain intensity reduction in painful
diabetic neuropathy,
55
and 0.11 for the same outcome in
bromyalgia.
56
In tapentadol trials in osteoarthritis or
chronic low back pain, patients tolerating treatment
with tapentadol or oxycodone and completing the trial
were likely those with good pain benet with increments
of 0.31.
57
In hand osteoarthritis, there was a strong
association between reduced pain and improved func-
tion.
58
In comparison, a systematic review of quality-
adjusted life years for estimating effectiveness of health
care reported utility gains from healthcare interventions
over 0.51.0 year.
58
Of 31 examples, only 9 (29%) had
1-year gains above 0.1, while 22 (71%) had gains well
below 0.1. This makes the quality of life gains obtained
with successful treatment of chronic pain very impor-
tant, placing them among the highest in medicine.
There is consistent evidence across chronic pain that
patients achieving good levels of pain relief, or achieving
low pain states, have major improvements in quality of
life.
Once it has been appropriately decided to signi-
cantly intervene and treat pain, choosing which inter-
vention to employ becomes the issue. When using the
most common chosen therapy, some formof NSAID, we
must consider the inherent risks of using these drugs for
their provided benet. One of the major risks of these
drugs, whether they are considered selective or nonse-
lective cyclooxygenase inhibitors, is related to adverse
gastrointestinal events of gastroduodenal ulcer forma-
tion, bleeding, perforation, obstruction, and death.
Although large amounts of data have been accumulated
to dene the hypertension risk, cardiovascular risks,
renal, and other myriad risks associated with chronic
NSAID use, the more common problem has been
consequent GI damage. Thus, assessing the GI risk of
the patient to be treated along with gastroprotective
strategies to mitigate it is an important part of the
clinical decision process.
Gastroprotective Strategies with PPI and High-Dose
H
2
A
As a starting point, we took a Cochrane review,
14
a U.K.
analysis from NICE,
59
and supplemented using an
electronic literature search for additional randomized
trials and then re-analyzed outcome data.
PPI. Seven trials in 6 reports compared PPI + NSAID
with placebo + NSAID.
6065
These trials lasted between
12 and 26 weeks, recruited 2,176 patients, of whom
between 6% and 100% had a prior history of ulcer;
naproxen was the most commonly used NSAID
(Table 3). Two additional trials reported in 2010
65
added 860 patients to the total, so that 40% of the data
analyzed were additional to the Cochrane review.
14
Table 2. Results from Meta-Analyses of Nonsteroidal Anti-Inammatory Drugs in Chronic Musculoskeletal Conditions
using Contemporary Evidence Standards and an Outcome Equivalent to at Least 50% Pain Intensity Reduction
Drug & Dose (mg)
Number of Percent with Outcome
Number Needed to Treat (NNT)
(95% CI) Trials Patients Active Placebo
Osteoarthritis12 weeks of treatment
Etoricoxib 60 3 711 44 23 4.7 (3.3 to 8.1)
Naproxen 1000 2 545 44 23 4.8 (3.3 to 8.5)
Etoricoxib 30 2 643 45 27 5.5 (3.9 to 9.3)
Celecoxib 200 2 722 39 22 5.8 (4.2 to 9.5)
Ibuprofen 2400 2 628 39 27 8.4 (5.1 to 24)
Ankylosing spondylitis6 weeks of treatment
Etoricoxib 120 2 185 55 15 2.5 (1.9 to 3.5)
Etoricoxib 90 2 196 55 15 2.5 (1.9 to 3.5)
Naproxen 1000 2 195 42 15 3.7 (2.5 to 6.6)
Chronic low back pain12 weeks of treatment
Etoricoxib 60 2 424 47 35 8.1 (4.6 to 33)
Etoricoxib 90 2 427 47 35 8.3 (4.7 to 33)
Outcome of 50% pain intensity reduction (PIR) at 12 weeks, or 50% reduction in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) at 6 weeks, and with withdrawal
for any reason taken as non response
NSAID, GPA, and BenetRisk 383
Various PPIs were used, including omeprazole, pantop-
razole, lansoprazole, and esomeprazole. Most trials
provided results for both gastric and duodenal ulcers,
although 1
63
provided results only for gastric ulcers,
which are more common than duodenal ulcers associ-
ated with NSAID use. The total number of upper GI
endoscopic ulcers was also reported except in two
studies;
63,65
for the latter, the total was assumed to be
the sum of gastric and duodenal ulcers, as the ve
studies reporting gastric, duodenal, and total upper GI
ulcers had totals that were the sum of gastric and
duodenal.
With NSAID + placebo, the incidence of upper GI
ulcers ranged between 15% and 50% (Figure 2). PPI
signicantly reduced the incidence of endoscopic ulcers,
however, described (Table 4). Using the outcome of all
upper GI endoscopic ulcers, there was a 65% reduction
in incidence across trials from 32% to 11%. For PPI vs.
placebo, the overall NNTp for total upper GI endo-
scopic ulcers was about 5, with an NNTp of about 7 for
gastric ulcers and 16 for duodenal ulcers (Table 4).
High-dose H
2
RA. Five trials in 4 reports compared
high-dose H
2
RA + NSAID with placebo + NSAID.
6669
These trials lasted between 12 and 52 weeks and
recruited 1,680 patients, of whom between 6% and
100% had a prior history of ulcer; ibuprofen was the
most commonly used NSAID (Table 3). Two additional
Table 3. Summary of Randomized Trials Evaluating Efcacy of Proton Pump Inhibitors (PPI) and H
2
RA for Protection
Against Endoscopic Ulcers with Nonsteroidal Anti-Inammatory Drugs (NSAIDs)
Reference
Patients
(N)
Previous Ulcers
(%)
Duration
(weeks) NSAID
GPA
(daily dose mg)
PPI
Bianchi Porro et al.
60
95 15 12 Diclofenac, ketoprofen,
indomethacin
Pantoprazole 40
Cullen et al.
61
168 24 26 Naproxen Omeprazole 20
Ekstrom et al.
62
177 24 12 Naproxen Omeprazole 20
Graham et al.
63
403 100 12 Ibuprofen, naproxen,
diclofenac, aspirin, piroxicam
Lansoprazole 15 or 30
Hawkey et al.
64
429 30 26 Diclofenac, ketoprofen, naproxen Omeprazole 20
Goldstein et al.
65
PN400-301 434 6 26 Naproxen Esomeprazole 40
Goldstein et al.
65
PN400-302 420 10 26 Naproxen Esomeprazole 40
High-dose H
2
A
Hudson et al.
66
78 29 24 Diclofenac Famotidine 80
Taha et al.
67
190 12 24 Diclofenac, naproxen,
indomethacin, ketoprofen, ibuprofen, fenbufen
Famotidine 80
Ten Wolde et al.
68
30 100 52 Diclofenac Ranitidine 600
Laine et al.
69
REDUCE-1 812 7 24 Ibuprofen Famotidine 80
Laine et al.
69
REDUCE-2 570 6 24 Ibuprofen Famotidine 80
GPA, gastroprotective agents.
0
10
20
30
40
50
60
0 10 20 30 40 50 60
Upper GI ulcers with high-dose H2A (%)
Upper GI ulcers with placebo (%)
0
500
1000
0
10
20
30
40
50
60
0 10 20 30 40 50 60
Upper GI ulcers with PPI (%)
Upper GI ulcers with placebo (%)
0
500
1000
Figure 2. Plot of upper gastrointestinal endoscopic ulcer rates with nonsteroidal anti-inammatory drug (NSAID) + gastroprotective
agents (GPA) vs. NSAID + placebo. Size of symbol is proportional to size of study (inset scale).
384 MOORE ET AL.
trials reported in 2010
69
added 1,382 patients to the
total, so that 82% of the data analyzed were additional
to the Cochrane review.
14
H
2
RAs used were famotidine
in four trials, and ranitidine in one. All provided results
for both gastric and duodenal ulcers, as well as total
number of upper GI endoscopic ulcers. One additional
trial published in Russian had only a 4-week duration,
but an English summary reported a 50% reduction in
endoscopic ulcers with diclofenac plus famotidine vs.
diclofenac alone in 224 patients, although based on
small numbers of events.
70
With NSAID + placebo, the incidence of upper GI
ulcers ranged between 18% and 54% (Figure 2). High-
dose H
2
RA signicantly reduced the incidence of endo-
scopic ulcers, however, described (Table 4). Using the
outcome of all upper GI endoscopic ulcers, there was a
46% reduction in incidence across trials from 24% to
11%. For high-dose H
2
RA vs. placebo, the overall
NNTp for total upper GI endoscopic ulcers was about 8,
with an NNTp of about 10 for gastric ulcers and 17 for
duodenal ulcers (Table 4).
Comparing PPI with High-dose H
2
RA. These indirect
comparisons of results with PPI and high-dose H
2
RA
showed a somewhat greater reduction in the incidence in
upper GI endoscopic ulcers with PPI than high-dose
H
2
RA, with a statistically lower (better) NNTp for PPI
than H
2
RA (z = 2.99, P = 0.003). The PPI studies
mostly used naproxen as the NSAID, while those with
high-dose H
2
RA mostly used ibuprofen (Table 3). We
know from observational studies that naproxen pro-
duces more GI problems than ibuprofen (Table 1) and
that tendency probably describes the higher incidence of
endoscopic ulcers with placebo in the PPI compared
with the H
2
RA studies. While the starting points were
different, the absolute risk of upper GI endoscopic ulcers
endoscopic ulcer with treatment was the same (at 11%)
with both gastroprotective interventions (Figure 3).
Direct comparisons of PPI and high-dose H
2
RAin the
same trial are lacking. There are comparative studies,
but in slightly different circumstances of healing estab-
lished NSAID or aspirin-associated ulcers rather than
those designed to determine prophylactic efcacy of
gastroprotective agents. One study compared esomep-
razole 20 mg or 40 mg with 300 mg (high dose)
ranitidine daily;
71
8-week healing rates were about
85% with esomeprazole compared with 76% with
ranitidine, with no statistical difference.
In other examples, a randomized study compared 20
and 40 mg omeprazole with 150 mg (low dose) raniti-
dine in patients using NSAIDs with established ulcers or
erosions.
72
Healing rates after 8 weeks were 80% with
Table 4. Summary of Analyses of Efcacy of Proton Pump Inhibitors (PPI) and H
2
RA in Studies Comparing Nonsteroidal
Anti-Inammatory Drugs (NSAID) + Gastroprotective Agents (GPA) with NSAID + Placebo, Over 12 weeks or Time
Nearest 12 weeks
Outcome vs. Placebo
Number of Percent Ulcers with
Relative Risk
(95% CI)
NNTp
95% CI) Trials Patients Active Placebo
PPI
Gastric ulcers 7 2,076 10 25 0.34 (0.27 to 0.42) 6.7 (55 to 8.6)
Duodenal ulcers 6 1,729 1 7 0.16 (0.08 to 0.29) 16 (12 to 24)
Upper GI ulcers 5 1,216 14 34 0.35 (0.28 to 0.43) 4.7 (3.8 to 6.1)
Upper GI ulcers (assumed) 7 2,076 11 32 0.30 (0.25 to 0.36) 4.8 (4.1 to 5.8)
High-dose H
2
A
Gastric ulcers 5 1,680 10 19 0.52 (0.40 to 0.66) 10 (7.5 to 17)
Duodenal ulcers 5 1,680 1 7 0.23 (0.13 to 0.41) 17 (13 to 28)
Upper GI ulcers 5 1,680 11 24 0.49 (0.39 to 0.61) 7.7 (5.9 to 11)
GI, gastrointestinal; NNTp, number needed to treat to prevent.
Note that for PPI, all upper GI ulcers were assumed to be sum of gastric and duodenal ulcers in two studies
PPI High-dose H2A
0
10
20
30
40
Percent
Upper GI ulcers at study end
GPA Placebo
Figure 3. Overall incidence of endoscopic ulcers with nonsteroi-
dal anti-inammatory drug plus gastroprotective agents or
placebo (percent).
NSAID, GPA, and BenetRisk 385
omeprazole compared with 63% with low-dose raniti-
dine, with a maintenance phase after healing yielding a
six-month ulcer-free rate of 72% for omeprazole and
59% for low-dose ranitidine. A similar comparison of
lansoprazole 30 mg with low-dose famotidine 40 mg in
patients with established ulcer using low-dose aspirin
demonstrated identical healing rates (89%) after
8 weeks.
73
Observational studies that examine bleeding
rates with NSAIDs nd a somewhat greater protective
effect with PPI than H
2
RA; for example in a Spanish
study, Lanas and colleagues
74
reported adjusted relative
risk of peptic ulcer bleeding of 0.33 (0.27 to 0.39) with
PPI compared to 0.65 (0.50 to 0.85) with H
2
RA, but
with no information about the actual drugs, and
particularly the dose of H
2
RA. Similar results are
reported with low-dose aspirin, but again with no
indications of GPA dose.
75
There is consistent evidence across indirect and direct
studies that the gastroprotective effects of PPI and high-
dose H
2
RA are broadly similar, but that low doses of
H
2
RA have lower effectiveness. There is no conclusive
evidence of greater PPI efcacy compared with high-
dose H
2
RA.
Although there are other gastroprotective strategies
including the addition of misoprostol to the NSAID
regimen or developing a combination medication, the
use of this medication is limited by dose-related symp-
toms directly related to the mechanism of action of
replacing prostaglandins within the GI tract. Thus,
when considering which gastroprotective therapy to use,
we must consider the information learned about adher-
ence to the medications offered.
Adherence to Gastroprotective Strategies
Prescribers Adherence to Guidance. A systematic
review of studies of adherence of prescribing gastropro-
tective agents (GPA) with NSAIDs conducted up to the
end of 2005 and including 911,000 NSAID users found
that GPAs were prescribed in about 26% of patients
taking NSAIDs and having at least one gastrointestinal
risk factor, like age, previous ulcers, etc.
11
An extension
of the search from 2006 to August 2012 identied 21
additional studies (Table 5) with over 1,034,000 addi-
tional NSAID users.
7696
As in the earlier systematic review, there was a range
of values for the percentage of patients using GPAs with
NSAIDs, and this reects differences in denitions of
GPA cover. For example, several studies examined not
just coprescribing, but the extent of coprescribing, with
at least 80% of the NSAID exposure time covered by
GPA dened as adequate.
82,86,87,92,95
There was a
tendency for smaller studies (fewer than 5,000 subjects)
to produce a somewhat better adherence of GPA
prescribing than larger studies (Figure 4).
Combining the data from these 21 studies with those
from the earlier systematic review (Figure 5), it becomes
clear that there is a much greater variability between
studies when they are smaller than when they are larger,
but considerable variability still exists even with large
studies.
Over time, GPA prescribing rates have increased. For
example, in a Dutch study, GPA prescribing with
NSAIDs increased from 40% in 2001 to 70% in
2007,
80
and in a study in three European countries,
under-use of GPA fell between 2000 and 2008.
93
That
increase is evident taking all the studies together; those
in the review to the end of 2005 reported a weighted
mean GPA prescribing rate of 26%, while the 21 later
studies published since 2005 reported 49%. Overall, the
rate was 38%.
Despite highly variable rates of adherence found
between studies, and despite the tendency over time for
adherence to prescribing guidance to increase, there is
consistent evidence that about half of patients with
gastrointestinal risk factors prescribed NSAIDs are not
prescribed adequate or any gastroprotection.
Patients Adherence to Prescribed GPA. The propor-
tion of patients who adhere to their coprescribed GPA is
known to fall rapidly within the rst year.
97
A more
recent study in Spain suggests short-termadherence with
GPA for NSAID use may be as high as 85%.
98
There is
clear evidence that lack of adherence is associated with
increased gastrointestinal harm.
92
Other Risks with NSAIDs and Pain
NSAIDs and coxibs are associated with other potential
risks, fracture,
99
and renal failure in older patients given
NSAIDs with longer half-lives.
100
The risk of fracture is
much higher with opioids than with NSAIDs, with an
incidence rate 5 times higher in older adults in a large
propensity-matched study;
101
hospital admission for
adverse events and all-cause mortality were also consid-
erably higher with opioids. Meta-analysis of random-
ized trials of NSAIDs and coxibs indicate a 45%
increased risk of a vascular event compared with
placebo, amounting to a 0.3% increased absolute risk
a year against a background risk of about 1% a year.
102
386 MOORE ET AL.
Similar risk was evident for all coxibs or NSAIDs, with
the exception of naproxen in these randomized trials, for
which there was no increased risk.
There is increasing evidence that the presence of
chronic pain, particularly severe pain
103,104
or pain
resulting in inactivity,
105
is associated with increased all-
cause mortality. Large, long-term observational studies
fail to corroborate increased cardiovascular risk with
NSAIDs; indeed, they suggest that long-term treatment
with NSAIDs or coxibs is associated with reduced
incidence of cardiovascular events and all-cause mor-
tality.
106,107
The degree of the reduction is substantial
and appears to be true of all cardiovascular events,
cardiovascular mortality, and all-cause mortality. NSA-
IDs and coxibs tend to have lower rates of signicant
harm than opioids in large-matched cohorts.
101
One
Table 5. Summary of Individual Studies and Meta-Analyses Published 2006 to 2012 Reporting Doctors Adherence to
Prescribing Guidelines for Patients Taking Nonsteroidal Anti-Inammatory Drugs (NSAID), and with at Least One GI
Risk Factor
Study Details Place Number
Adherence
(prescribed appropriate
GPA)
Moore et al.
11
Systematic review of GPA adherence to
end 2005. Data from observational studies
Worldwide, mainly
N America, Europe
1.6 million, of
whom 911,000
NSAID users
26%
Bell et al.
76
Survey of nursing home long-term residents Finland 1,087 total 22%
Bianco et al.
77
Nationwide GP survey Italy 3,943 81%
Cot e et al.
78
Review of patients discharged from
medical service over 3 months
U.S.A. 338 46%
Doherty et al.
79
Record review of hospital inpatients Ireland 160 58% at end
only 60 to 70% with
several risk factors
Helsper et al.
80
Retrospective cohort of medical records database The Netherlands 1.5 million, 7.5%
using NSAIDs
40% in 2001
70% in 2007
Johnell and Fastbom
81
National prescribed drug register Sweden 41,626 NSAID users 22%
Koncz et al.
82
Retrospective analysis of national GP database U.K. 26,371 NSAID users Adequate
gastroprotection 20%
High risk 20% to 38%
Lanas et al.
83
Patients visiting a national health service
on 1 day with osteoarthritis
Spain 17,105 56% low risk to 92%
high risk with NSAID
33% to 76% with coxib
Lanas et al.
84
Retrospective medical record study Spain 2,106 90%
Ljung et al.
85
Nationwide registry study for persons
aged 65 years and older
Sweden 1.5 million
257,963 using NSAIDs
40%
Lopez-Pintor
and Lumbreras
86
Cross-sectional study of community pharmacies Spain 670 64%
(but only 20% had
appropriate protection)
Morini et al.
87
Cross-sectional studies of NSAID users in
primary care over 1 week
Italy 869 Appropriate protection
in 34%
Pasina et al.
88
Analysis of prescription health database Italy Over 1 million
population of
whom 21,553 were
regular NSAID
users 35 years
17%
Thi en and Schwalm
89
Cross-sectional analysis of patients in
primary care
France 1,002 39%
Tsumura et al.
90
NSAID users who had undergone upper
GI endoscopy
Japan 128 regular users 84%
Valkhoff et al.
91
Analysis of integrated primary care database The Netherlands 50,126 39%
Valkhoff et al.
93
Casecontrol study using information from
3 primary care databases for coxib treatment
The Netherlands,
U.K., Italy
14,146 > 80% cover in 49%
taking coxib for
1 month
Valkhoff et al.
93
Population-based cohort study in 3 European
countries
U.K., Italy, The
Netherlands
617,000 total NSAID
users, 314,000 with
GI risk factor
Under-use of GPA in 66
to 76% in 2008, reducing
over time
van Soest et al.
94
Nested casecontrol study of new NSAID
users with GI risk factors
The Netherlands 38,201 15%
van Soest et al.
95
Nested casecontrol study of new NSAID users
aged 50 years who also used a GPA
The Netherlands,
U.K., Italy
61,8684
117,307 nsNSAID
plus GPA
> 80% cover in 53%
taking coxib for
1 month
Van der Linden et al.
96
Retrospective analysis of prescription database The Netherlands 58,770 20%
GPA, Gastroprotective agents.
NSAID, GPA, and BenetRisk 387
possible explanation for the association between chronic
severe pain and increased all-cause mortality is lack of
mobility, and the removal of the cardioprotective
benets of active living, although this is no more than
speculative.
Other Risks with GPA
Rare but serious harm may also be associated with long-
term use of gastroprotective agents. A number of
systematic reviews have examined risk with GPAs,
particularly PPIs.
PPIs. Proton pump inhibitors have been associated
with higher rates of fracture. A substantial number of
studies and meta-analyses have demonstrated a modest
increase with PPIs but not other acid-suppressing
medicines.
108115
The link between PPI use and frac-
tures has been downplayed because there is no proven
mechanism. The reported magnitude of the risk eleva-
tion associated with the use of PPIs was only weak, and
the likelihood of residual confounding despite adjust-
ment for known comorbidities and drug use cannot be
ruled out.
113,116
A number of other potential risks have been associ-
ated with long-term use of PPIs, including cancer,
enteric infections (mainly Clostridium difcile-associ-
ated diarrhea), pneumonia, hypomagnesaemia, and
drug interactions, particularly with clopidogrel.
117,118
All have evidence of some effects, mainly moderate in
magnitude, and with the possibility of confounding by
indication. These are not reviewed in detail here, but are
mentioned for completeness. Concern regarding the
safety of PPIs has been highlighted in a number of recent
U.K. Medicines and Healthcare Regulatory Agency
(MHRA) safety updates.
H
2
RAs. We could not nd reviews or large studies
indicating increased risks associated with long-term
H
2
RA use and no increased risk of colorectal ade-
noma.
119
Patient and Physician Attitudes to Risk and Benet
While the requirement for risk minimization is clear, the
purpose for prescribing NSAIDs is to reduce pain, the
symptom (probably with decreased function) that brings
the patient to the clinic in the rst place. This makes it
expedient to examine the risk and benet from the
patients perspective.
Patients with chronic conditions are willing to accept
relatively high levels of risk of harm to obtain effective
therapy, despite the signicant barriers to describing
benet and risk in terms understood by patients in the
clinical setting.
120,121
Table 6 summarizes results from
recent studies of patient attitude to risk and benet in a
variety of chronic conditions, including menopausal
ushing and sweats,
122
Crohns disease,
123
osteoarthri-
tis,
124,125
multiple sclerosis,
126
idiopathic thrombocyto-
penic purpura,
127
and irritable bowel syndrome.
128
They are characterized by patients regarding maximum
acceptable risk of harm for successful treatment of 1 in
300 to 1 in 30 to get successful treatment. The
<25% 25-49% 50-74% 75%
0
1
2
3
4
5
Number of studies
Percentage cover with GPA
Small
Large
Figure 4. Degree of adherence to gastroprotective agents pre-
scribing with nonsteroidal anti-inammatory drugs according to
study size (smaller studies had fewer than 5,000 subjects each).
0
200000
400000
600000
800000
0 20 40 60 80 100
Number of patients using NSAID
Percent prescribed GPA
Figure 5. Prescribing of gastroprotective agents with nonsteroi-
dal anti-inammatory drugs in patients with at least one
gastrointestinal risk factor in individual studies.
388 MOORE ET AL.
acceptable risk is typically similar to or higher than the
actual risk.
Physicians see things differently, especially in the
treatment of arthritis. A survey in the U.K. found that
physicians graded a very substantial reduction in pain
(from 75/100 mm to 25/100 mm, that is from severe to
mild pain) as less important than an increased risk of
heart attack from 0% to 1.5% (roughly 1 in 70 risk).
Physicians were willing to accept an increased risk of
bleeding of 0.7% (roughly a 1 in 140 risk) for a
reduction in pain from 75/100 mm to 25/100 mm, that
is, fromsevere to moderate pain.
129
It would appear that
benets generally regarded as substantial or moderate in
importance
43
are neglected compared with small or
moderate increases in absolute risk.
DISCUSSION
Important issues in clinical practice are to establish that
the NSAID or coxib prescribed delivers good pain relief
and that these patients, who may need to use NSAIDs or
coxibs in the long term, are prescribed gastroprotection
and use it. The evidence on both counts gives cause for
concern. A 2011 survey of 1,260 osteoarthritis patients
across 6 European Union countries showed that only
46% experienced adequate pain relief;
130
those with
inadequate pain relief are put at risk for no benet. The
proportion of patients who adhere to their coprescribed
GPA is known to fall rapidly within the rst year.
97
Clinical guidance on gastroprotection is consistent
across many guidelines. When an NSAID is prescribed
and there is an increased risk of gastrointestinal harm,
some form of gastroprotection should be prescribed.
The NICE guidance on osteoarthritis, for instance,
suggests coprescription with a PPI in every patient,
irrespective of risk and whether the patient is prescribed
an NSAID or a coxib.
15
The issues are as follows:
1. To ensure patients have a good level of pain relief.
Any single NSAID or coxib will deliver good pain
Table 6. Studies Reporting Patients Judgement of Acceptable Risk with Treatment in Chronic Conditions
Reference Study Design Acceptable Risk Probable Actual Risk
Johnson et al.
122
Internet questionnaire survey of
523 U.S. women regarding risks of
cancer or heart disease
for various levels of benets for hot
ushes, sweats and
increased fracture risk
Maximum acceptable risk was:
Heart attack, 1 in 50 to 1 in 30
Cancer, 1 in 140 to 1 in 70
Heart attack 1 in 250
Cancer 1 in 250
Johnson et al.
123
Survey of 580 U.S. patients with Crohns
disease, and attitudes to serious infection,
lymphoma, and progressive multifocal
leukoencephalopathy related to moderate to
mild or severe to remission changes
About 50% of patients would
accept risk of 1 in 200 a year for
change in symptoms from
moderate to mild, and 80% would
accept 1 in 200 risk for change
from severe to remission
Risk of progressive multifocal
leukoencephalopathy in
persons with autoimmune
disorders in below 1 in 1,000
Richardson et al.
124
196 Canadian patients with OA, and attitudes
to risk of increased heart attack or GI bleed
for 2 or 5 point (out of 10) pain reduction
About 70% willing to accept increased
risk of both, with about 20% not
willing to accept any increased risk
Maximum acceptable risks of the order
of 1 in 50
Depends on drug, but
probably less than 1 in 1,000
Johnson et al.
126
651 U.S. patients with multiple sclerosis
presented with choices of treatment
benets and associated risks
Maximum acceptable risks for liver
failure, leukaemia, and progressive
multifocal leukoencephalopathy were 1 in
300 to 1 in 100 for various levels of benet
Natalizumab has reported
incidence of 1 case of
progressive multifocal
leukoencephalopathy per
384 MS patients
Hauber et al.
127
1,542 patients with chronic idiopathic
thrombocytopaenic purpura and risk of
thromboembolism
Maximum acceptable risk about 1
in 50 for > 50% chance of treatment success
Risk of any venous
thromboembolism is
about 1 in 50 following
splenectomy
Johnson et al.
128
589 U.S. women with diarrhoea predominant
irritable bowel syndrome and attitudes to
risk of impacted bowel, severe colitis, and
perforated bowel for different levels of
symptom relief
Maximum acceptable risk was 1 in
100 to 1 in 30 for good improvement
or complete symptom relief
Incidence of ischaemic
colitis with treatment
about 1 in 2,000, and
serious gastrointestinal
complications about
1 in 1,000
Hauber et al.
125
294 U.K. patients with OA questioned about
the benets of different outcomes and risks
For improvement in ambulatory pain to
mild pain or less, acceptable risk
for bleeding ulcer, heart attack, or stroke
was around 1 in 100 to 1 in 50
Actual increased risks
probably 1 in 1,000 or
less for any treatment
NSAID, GPA, and BenetRisk 389
relief to only about 25% of those patients who try
it.
2. How best to ensure that gastroprotection is
guaranteed for the NSAID or coxib that delivers
good pain relief. One argument for the use of
coxibs was convincing evidence that they did
deliver reduced gastrointestinal harm across a
range of different outcomes
11
and, at doses used,
had at least equal efcacy.
46
Fixed-dose combi-
nation products of esomeprazole plus naproxen,
omeprazole plus ketoprofen, and high-dose
famotidine plus ibuprofen are available. There-
fore, there is a range of options that could deliver
good pain relief for patients and provide reliable
gastrointestinal protection while they are being
taken.
The knowledge that pain relief and other benets of
successful treatment have a bimodal distribution can
simplify the assessment of benet and risk. For those
who are nonresponders, without signicant reduction in
pain or who have intolerable adverse events that impede
any benets because they prevent the tablets being
taken, risk should be irrelevant because therapy should
stop. Those who are responders will have large benets
to set against any potential risk, and while they should
be cognisant of the risk, the evidence is that most would
choose benet over risk.
For an individual patient with chronic musculoskel-
etal pain, the key is to nd the NSAIDor coxib that gives
both good pain reliefs with tolerable adverse events.
If an NSAID works for that individual patient, we know
that gastroprotection as concomitant but separate PPI,
misoprostol, or high-dose H
2
RA is often neither pre-
scribed nor taken. The problem can be overcome for
some NSAIDs because single tablet combination thera-
pies are available for naproxen (Vimovo

, naproxen
plus esomeprazole; AstraZeneca UL Ltd, Luton, UK),
ibuprofen (DUEXIS

, ibuprofen plus high-dose famoti-

dine; Horizon Pharma, Deereld, IL, USA), and keto-
profen (Axorid

, ketoprofen plus omeprazole; Meda

AB, Solna, Sweden). These combination products are
variably available in the U.K. and Europe, and U.S.A.
and Canada. If it is a coxib that provides good pain
relief, then gastroprotection is built in, but guidance
sometimes recommends GPA with coxibs. Finding a
strategy that delivers gastroprotection is an important
component of improving the balance of benet over risk
with NSAIDs for chronic musculoskeletal pain.
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